Heterocyclic molecular scaffolds containing the trifluoromethyl functional group have become increasingly common in biologically active compounds targeted by the pharmaceutical industry. Chemotherapeutics ranging from antidepressants to anticancer agents have successfully utilized the incorporation of trifluoromethyl groups due to the unique properties their presence elicits. For this reason, there has been a consistent drive within the chemical community towards the development of chemical methods for the installation of the trifluoromethyl group into pharmaceutically relevant heterocyclic scaffolds. The proposed research aims to develop and refine novel chemical strategies for site-selective trifluoromethylations of aromatic heterocycles through a combination of high-throughput screening and mechanistic analysis. High-throughput screening will efficiently test and push the limits of a recently reported, but underdeveloped trifluoromethylatio protocol that has been show to have significant advantages over previous methods. DFT calculations will be performed in tandem with reaction screens to develop a predictive model of reactivity and site-selectivity based on ground-state substrate properties. Mechanistic investigation involving kinetic analysis and kinetic isotope effect studies will lead to better understanding of this important reaction class, allowing for further development and the discovery of related processes. Finally, the long term goal of the proposed research is the development of a suite of general experimental procedures for the trifluoromethylation of a variety of heterocyclic classes in high yield with high site-selectivity. The development of robust chemical strategies for the selective installation of trifluoromethyl groups into pharmaceutically relevant scaffolds would have a significant and immediate impact on the medical community as trifluoromethyl- containing chemotherapeutics may be targeted more efficiently and in greater numbers by medicinal chemists and pharmaceutical industries.